Locomotor Recovery after Spinal Cord Injury: a Multidisciplinary Investigation of the Role and Potential of Preserved Tissue

Abstract Background Spinal cord injury is devastating for its victims because of the resulting motor, sensory and autonomic deficits, i.e., paraplegia and tetraplegia. The different deficits are mainly due to the interruption of the long white matter tracts which connect the supraspinal central nervous system to the spinal cord. In many cases, the interruption is partial and some recovery may be observed. The preserved spinal cord tissue plays a role in the recovery which, to date, has only been incompletely elucidated. The preserved spinal cord tissues have been investigated in the present work from two angles. The first part describes an attempt to recruit the locomotor generator of the sub-lesional cord, using several therapeutic strategies, in order to improve locomotor recovery. The second part describes a new approach for the investigation of the injury site and the preserved white matter; correlating magnetic resonance imaging and histology with locomotor recovery. Methods Subdural balloon compression was used in the rat to induce incomplete spinal cord lesions which allow partial locomotor recovery. Locomotion was assessed with a widely employed, detailed behavioural scale. In the first set of experiments, physiotherapy (body weight supported treadmill training), repetitive transcranial magnetic stimulation (rTMS), and monoaminergic pharmacotherapy (clonidine and fluoxetine) were used individually or in combination, five days a week, over several weeks. Spinal cords were analysed for histological and immunohistochemical correlates of recovery, including sub-lesional serotonin content. In the second set of experiments, experimental high field magnetic resonance imaging (MRI) was used post-mortem to investigate the spinal cord lesion and spared white matter. A comparison was then made between the MRI and subsequent histological data. Morphometric parameters assessing the lesion extent, spinal cord atrophy, and white matter sparing were correlated with locomotor function. In a supplementary post-mortem MRI investigation, an explanted sample of human sub-lesional thoracic cord was analysed after a severe cervical spinal cord injury. Results Body weight supported treadmill training had a clear beneficial effect when initiated early after injury. Repetitive TMS also appears to increase locomotor recovery after low thoracic spinal cord injury, associated with an increase of serotoninergic innervation of the sub-lesional spinal cord segment. Combining rTMS with clonidine therapy appeared to have synergistic positive effects on locomotor recovery, but no statistically significant results could be obtained, due to the variability of the observed locomotor scores. Histology of the cords in the latter experiment did not allow sufficient anatomical or quantitative comparison of white matter sparing, a potential reason for the behavioural variability. In the subsequent series of untreated rats, post-mortem MRI of the spinal cord precisely showed the lesion size and topography, as well as white matter sparing, with high spatial precision. MRI could differentiate between lesion components. The evolution of the lesion was followed from the acute to the chronic stage. Different morphometric parameters were statistically significantly correlated with locomotor function. In the human spinal cord sample, the almost complete sub-lesional degeneration of the white matter tracts was precisely demonstrated with the same technique. Conclusion The present investigations confirm and extend the notion that partially preserved spinal cord tissue plays a key role in locomotor recovery after spinal cord injury. The intrinsic locomotor circuitry of the spinal cord is a promising therapeutic target for various strategies which can be combined and are potentially rapidly applicable in the clinical situation, as all the investigated treatments are already used in humans for different indications. The quantity and topography of white matter sparing is of major importance in locomotor recovery, and it can be precisely assessed with post-mortem MRI.Résumé Introduction La tétra- et la paraplégie résultant d’un traumatisme médullaire sont principalement dues à l’interruption des voies longues qui connectent les centres supraspinaux aux circuits intramédullaires. La majorité des lésions médullaires sont anatomiquement incomplètes et une récupération fonctionnelle peut être observée dans bon nombre de cas. Le rôle du parenchyme médullaire épargné dans la récupération n’est que partiellement compris—que ce soit celui de la substance blanche périlésionnelle ou celui des circuits médullaires situés à distance de la lésion. Premièrement, nous avons tenté de recruter les circuits médullaires sous-lésionnels par différentes stratégies thérapeutiques, dans le but d’améliorer la récupération locomotrice. Ensuite, nous avons mis au point une technique d’imagerie par résonance magnétique (IRM) permettant l’étude de la substance blanche préservée et corrélé les images obtenues et l’histologie à la récupération fonctionnelle. Méthodes Après un traumatisme médullaire expérimental incomplet, nous avons suivi l’évolution locomotrice au moyen d’une échelle comportementale détaillée, largement utilisée. Dans la première partie du travail, différents groups de rats ont été traités pendant plusieurs semaines par physiothérapie (entraînement sur tapis roulant avec support du poids du corps), par stimulation transcrânienne magnétique répétitive (STMr), et par substances monoaminergiques (clonidine et fluoxétine), seuls ou combinés. Des analyses histologiques et immunohistochimiques des moelles épinières ont été réalisées, visant notamment à mettre en évidence la sérotonine dans le parenchyme sous-lésionnel. Dans la deuxième partie du travail, nous avons étudié la lésion médullaire et la substance blanche épargnée par IRM post-mortem, comparant sa précision à celle de l’histologie standard. L’étendue de la lésion, le degré d’atrophie médullaire et la quantité de parenchyme préservé ont été mesurés et corrélés au comportement locomoteur. Dans une étude supplémentaire, un échantillon de moelle épinière humaine thoracique sous-lésionnelle a été analysé par la même technique d’IRM. Résultats L’entraînement par tapis roulant précoce potentialise la récupération fonctionnelle. La STMr semble également avoir un effet favorable sur la récupération dans les lésions médullaires thoraciques basses, augmentant l’innervation sérotoninergique de la moelle épinière sous-lésionnelle. Parmi les stratégies thérapeutiques combinées, nous avons également observé que les rats traités par STMr et clonidine montraient globalement une meilleure récupération locomotrice. Toutefois, cet effet n’était pas statistiquement significatif, en raison d’une variabilité trop importante des scores locomoteurs—possiblement attribuable à une hétérogénéité de préservation de substance blanche au sein des groupes expérimentaux. L’histologie n’a cependant pas permis de confirmer cette hypothèse. Chez les rats non traités, dans la deuxième partie du travail, l’IRM post-mortem de haute résolution nous a permis d’évaluer très précisément la lésion médullaire et la substance blanche préservée. Elle a également permis de distinguer différents composants histologiques de la lésion et son évolution du stade aigu au stade chronique. Les paramètres morphométriques ont pu être corrélés significativement au comportement locomoteur. Dans la moelle épinière humaine, une dégénérescence quasi complète des voies descendantes sous-lésionnelles a été démontrée. Conclusion La moelle épinière partiellement préservée joue un rôle clé dans la récupération locomotrice après un traumatisme médullaire. Les circuits locomoteurs intrinsèques sont une cible prometteuse pour différentes stratégies thérapeutiques qui peuvent être combinées et qui sont potentiellement rapidement applicables en clinique, puisque tous les traitements investigués sont déjà utilisés à d’autres fins chez l’homme. La quantité et la topographie de substance blanche épargnée sont d’une importance primordiale dans la récupération fonctionnelle, et celles-ci peuvent être précisément étudiées par l’IRM post-mortem

Modélisation micro-mécanique des milieux granulaires non saturés

Un modèle tridimensionnel polydisperse aux éléments discrets a été développé afin d'étudier le comportement des milieux granulaires non saturés. La présence d'eau interparticulaire est prise en compte grâce à l'introduction de forces spécifiques, décrites dans le cadre de la théorie de la capillarité. Afin de considérer les mécanismes de transfert d'eau au sein du milieu, le modèle est piloté en succion: à chaque niveau de succion, les forces capillaires et la teneur en eau sont calculées à partir d'une résolution numérique de l'équation de Laplace-Young

The expression of B7-H3 isoforms in newly diagnosed glioblastoma and recurrence and their functional role.

Short survival of glioblastoma (GBM) patients is due to systematic tumor recurrence. Our laboratory identified a GBM cell subpopulation able to leave the tumor mass (TM) and invade the subventricular zone (SVZ-GBM cells). SVZ-GBM cells escape treatment and appear to contribute to GBM recurrence. This study aims to identify proteins specifically expressed by SVZ-GBM cells and to define their role(s) in GBM aggressiveness and recurrence. The proteome was compared between GBM cells located in the initial TM and SVZ-GBM cells using mass spectrometry. Among differentially expressed proteins, we confirmed B7-H3 by western blot (WB) and quantitative RT-PCR. B7-H3 expression was compared by immunohistochemistry and WB (including expression of its isoforms) between human GBM (N = 14) and non-cancerous brain tissue (N = 8), as well as newly diagnosed GBM and patient-matched recurrences (N = 11). Finally, the expression of B7-H3 was modulated with short hairpin RNA and/or over-expression vectors to determine its functional role in GBM using in vitro assays and a xenograft mouse model of GBM. B7-H3 was a marker for SVZ-GBM cells. It was also increased in human GBM pericytes, myeloid cells and neoplastic cells. B7-H3 inhibition in GBM cells reduced their tumorigenicity. Out of the two B7-H3 isoforms, only 2IgB7-H3 was detected in non-cancerous brain tissue, whereas 4IgB7-H3 was specific for GBM. 2IgB7-H3 expression was higher in GBM recurrences and increased resistance to temozolomide-mediated apoptosis. To conclude, 4IgB7-H3 is an interesting candidate for GBM targeted therapies, while 2IgB7-H3 could be involved in recurrence through resistance to chemotherapy

Distribution of Psychological Instability Among Surgeons.

peer reviewed[en] BACKGROUND: High emotional instability (i.e., neuroticism) is associated with poor mental health. Conversely, traumatic experiences may increase neuroticism. Stressful experiences such as complications are common in the surgical profession, with neurosurgeons being particularly affected. We compared the personality trait neuroticism between physicians in a prospective cross-sectional study. METHODS: We used an online survey using the Ten-Item Personality Inventory, an internationally validated measure of the 5-factor model of personality dimensions. It was distributed to board-certified physicians, residents, and medical students in several European countries and Canada (n = 5148). Multivariate linear regression was used to model differences between surgeons, nonsurgeons, and specialties with occasional surgical interventions with respect to neuroticism, adjusting for sex, age, age squared, and their interactions, then testing equality of parameters of adjusted predictions separately and jointly using Wald tests. RESULTS: With an expected variability within disciplines, average levels of neuroticism are lower in surgeons than nonsurgeons, especially in the first part of their career. However, the course of neuroticism across age follows a quadratic pattern, that is, an increase after the initial decrease. The acceleration of neuroticism with age is specifically significant in surgeons. Levels of neuroticism are lowest towards mid-career, but exhibit a strong secondary increase towards the end of the surgeon's career. This pattern seems driven by neurosurgeons. CONCLUSIONS: Despite initially lower levels of neuroticism, surgeons suffer a stronger increase of neuroticism together with age. Because, beyond well-being, neuroticism influences professional performance and health care systems costs, explanatory studies are mandatory to enlighten causes of this burden

The management of unruptured intracranial aneurysms

peer reviewe

Solitary fibrous tumour of the vagus nerve.

We describe the complete removal of a foramen magnum solitary fibrous tumour in a 36-year-old woman. It originated on a caudal vagus nerve rootlet, classically described as the 'cranial' accessory nerve root. This ninth case of immunohistologically confirmed cranial or spinal nerve SFT is the first of the vagus nerve